Perinatal depression, defined as major depressive episodes that occur either during pregnancy or within the first 6 months postpartum, can have devastating consequences for the woman, her children and her family. In particular, postpartum depression (PPD) has a prevalence rate of approximately 10%, making it one of the most common complications of both the prenatal and postpartum period. The pathogenesis of PPD is likely a complicated interplay of alterations in HPA stress axis reactivity mediated by genetic contributions. Our goal is to integrate two promising models of psychiatric illness: psychoneuroendocrinology and genetics. The basis for our conceptual model has two main hypotheses: 1) change in levels rather than direction of change of gonadal hormones may trigger mood disorders; 2) genetic variants in stress axis reactivity may predispose to depression in times of flux of gonadal hormones. My long-term career goal is to understand the pathogenesis of PPD, so that an optimal screening strategy that prospectively identifies those at risk of PPD can be developed. PPD may be a more homogeneous subset of major depressive disorder (MDD) suggested by its linkage to a puerperal endocrine trigger that is more amenable to searches for biomarkers. In Aim 1, we will compare HPA axis stress reactivity using both physiological (dexamethasone/CRH) and psychological (Trier Social Stress Test) challenges in euthymic women with a history of PPD, women with a history of non-puerperal MDD, and control women without a history of MDD. In Aim 2, we will conduct secondary analyses of an existing genomewide association dataset for PPD. All 3,540 subjects are from the Netherlands and were genotyped by Perlegen Sciences for 435,291 SNPs that tag common genetic variation in Europeans as part of the Foundation for the NIH GAIN study of MDD. Specifically, we will: a) conduct PPD phenotyping in GAIN MDD cases; b) perform an hypothesis-driven association of PPD for SNPs (36 candidate genes; 572 SNPs) in three groups, (women with a history of MDD (non-puerperal), women with a history of MDD and PPD, and normal controls); and c) using all other SNPs not part of Aim 2b (434,719 SNPs), perform a hypothesis-generating genomewide association study (GWAS) of PPD. RELEVANCE (See instructions): The public health relevance of this research is that its successful completion could allow for identification of specific markers for screening of PPD in women during the perinatal period. The disease burden of PPD is high and is a large source of health care costs. We propose to conduct cutting edge biomedical research that may allow us to identify and intervene in more productive, prospective ways for women at risk for PPD.